tbuckley/cabot-search huggingface dataset:
Continuous theta-burst stimulation enhances and sustains neurogenesis following ischemic stroke
Authors: Xuemei Zong, Jie Gu, Siqi Zhou, Ding Ding, Yuting Hu, Lorelei Tucker, Zhihai Huang, Deqin Geng, Dianshuai Gao
Journal: Theranostics (2022)

Rationale: Previous work has indicated that continuous theta-burst stimulation (cTBS), a modality of transcranial magnetic stimulation (TMS), may provide neuroprotection and improve neurological function after stroke by preserving the blood-brain barrier, altering glial polarization phenotypes, and supporting peri-infarct angiogenesis.The present study was performed to examine whether cTBS, a noninvasive neurostimulation technique, promotes neurogenesis in a photothrombotic (PT) stroke rat model and contributes to functional recovery.Methods: Beginning 3 h or 1 week after the induction of PT stroke, once-daily 5-min cTBS treatments were applied to the infarcted hemisphere for 6 days.Samples were collected 6 days, 22 days, and 35 days after PT stroke.Fluorescent labeling, Western blotting, and behavioral tests were performed accordingly.Results: We found that cTBS therapy significantly expanded the pool of neural progenitor cells (NPCs) and newly generated immature neurons in the cortical peri-infarct region after PT stroke.Likewise, the amount of DCX-positive immature neurons in the peri-infarct area was markedly elevated by cTBS.Application of cTBS strikingly diminished the PT-induced loss of NPCs and newly-formed neurons.In addition, the amount of newly generated mature neurons in the peri-infarct zone was significantly promoted by cTBS.Intriguingly, cTBS reduced reactive gliogenesis significantly while promoting oligodendrogenesis and preserving myelination.Mechanistic studies uncovered that cTBS upregulated brain-derived neurotrophic factor (BDNF) and fibroblast growth factor 2 (FGF2).Finally, cTBS-treated animals displayed improved motor functions.To be noted, temozolomide (TMZ), a drug that has been previously used to suppress neurogenesis, could reverse the beneficial effects of cTBS.Conclusions: Our findings provide new insight into the mechanism by which cTBS promotes functional recovery from stroke.We demonstrated that cTBS effectively enhances and sustains neurogenesis after PT stroke.Both early and delayed cTBS treatment could improve the survival of newly generated neurons and functional recovery, and inhibition of neurogenesis could reverse these therapeutic benefits.Mechanistically, cTBS was effective in upregulating the release of neurotrophic factors, protecting NPC and immature neurons, as well as suppressing excessive gliogenesis.
Identification of early invisible acute ischemic stroke in non-contrast computed tomography using two-stage deep-learning model
Authors: Jun Lu, Yiran Zhou, Wenzhi Lv, Hongquan Zhu, Tian Tian, Su Yan, Yan Xie, Di Wu, Yuanhao Li, Yufei Liu, Luyue Gao, Wei Fan, Yan Nan, Shun Zhang, Xiaolong Peng, Guiling Zhang, Wenzhen Zhu
Journal: Theranostics (2022)

Rationale: Although non-contrast computed tomography (NCCT) is the recommended examination for the suspected acute ischemic stroke (AIS), it cannot detect significant changes in the early infarction.We aimed to develop a deep-learning model to identify early invisible AIS in NCCT and evaluate its diagnostic performance and capacity for assisting radiologists in decision making.Methods: In this multi-center, multi-manufacturer retrospective study, 1136 patients with suspected AIS but invisible lesions in NCCT were collected from two geographically distant institutions between May 2012 to May 2021.The AIS lesions were confirmed based on the follow-up diffusion-weighted imaging and clinical diagnosis.The deep-learning model was comprised of two deep convolutional neural networks to locate and classify.The performance of the model and radiologists was evaluated by the area under the receiver operator characteristic curve (AUC), sensitivity, specificity, and accuracy values with 95% confidence intervals.Delong's test was used to compare the AUC values, and a chi-squared test was used to evaluate the rate differences.Results: 986 patients (728 AIS, median age, 55 years, interquartile range [IQR]: 47-65 years; 664 males) were assigned to the training and internal validation cohorts.150 patients (74 AIS, median age, 63 years, IQR: 53-75 years; 100 males) were included as an external validation cohort.The AUCs of the model were 83.61% (sensitivity, 68.99%; specificity, 98.22%; and accuracy, 89.87%) and 76.32% (sensitivity, 62.99%; specificity, 89.65%; and accuracy, 88.61%) for the internal and external validation cohorts based on the slices.The AUC of the model was much higher than that of two experienced radiologists (65.52% and 59.48% in the internal validation cohort; 64.01%and 64.39% in external validation cohort; all P < 0.001).The accuracy of two radiologists increased from 62.00% and 58.67% to 92.00% and 84.67% when assisted by the model for patients in the external validation cohort.Conclusions: This deep-learning model represents a breakthrough in solving the challenge that early invisible AIS lesions cannot be detected by NCCT.The model we developed in this study can screen early AIS and save more time.The radiologists assisted with the model can provide more effective guidance in making patients' treatment plan in clinic.
Emerging roles of extracellular vesicle-associated non-coding RNAs in hypoxia: Insights from cancer, myocardial infarction and ischemic stroke
Authors: Dirk M. Hermann, Wenqiang Xin, Mathias Bähr, Bernd Giebel, Thorsten R. Doeppner
Journal: Theranostics (2022)

Hypoxia is a central pathophysiological component in cancer, myocardial infarction and ischemic stroke, which represent the most common medical conditions resulting in long-term disability and death. Recent evidence suggests common signaling pathways in these diverse settings mediated by non-coding RNAs (ncRNAs), which are packaged in extracellular vesicles (EVs) protecting ncRNAs from degradation. EVs are a heterogeneous group of lipid bilayer-covered vesicles released from virtually all cells, which have important roles in intercellular communication. Recent studies pointed out that ncRNAs including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are selectively sorted into EVs, modulating specific aspects of cancer development, namely cell proliferation, migration, invasion, angiogenesis, immune tolerance or drug resistance, under conditions of hypoxia in recipient cells. In myocardial infarction and stroke, ncRNAs shuttled via EVs have been shown to control tissue survival and remodeling post-hypoxia by regulating cell injury, inflammatory responses, angiogenesis, neurogenesis or neuronal plasticity. This review discusses recent evidence on EV-associated ncRNAs in hypoxic cancer, myocardial infarction and stroke, discussing their cellular origin, biological function and disease significance. The emerging concept of lncRNA-circular RNA/ miRNA/ mRNA networks is outlined, upon which ncRNAs synergistically respond to hypoxia in order to modify disease responses. Particular notion is given to ncRNAs participating in at least two of the three conditions, which revealed a large degree of overlaps across pathophysiological conditions. Possible roles of EV-ncRNAs as therapeutic products or theranostic markers are defined.
Mesoscale visualization of three-dimensional microvascular architecture and immunocyte distribution in intact mouse liver lobes
Authors: Zheng Liu, Mengli Xu, Songlin Huang, Qi Pan, Chong Liu, Fanxin Zeng, Zhan Fan, Yafang Lu, Jialu Wang, Jinxin Liu, Xinlin Li, Qingming Luo, Zhihong Zhang
Journal: Theranostics (2022)

Rational:The complex vascular architecture and diverse immune cells of the liver are critical for maintaining liver homeostasis.However, quantification of the network of liver vasculature and immunocytes at different scales from a single hepatic lobule to an intact liver lobe remains challenging.Methods: Here, we developed a fast and fluorescence-preserving transparency method, denoted liver-CUBIC, for systematic and integrated analysis of the microcirculation and the three-dimensional distribution of dendritic cells (DCs)/macrophages in intact liver lobes.Results: Whole-mount imaging at mesoscale revealed that the hepatic classical lobule preferred the oblate ellipsoid morphology in the mouse liver and exhibited hepatic sinusoids with heterogeneous arrangement and intricate loop structure.Liver fibrosis not only induces sinusoidal density increase but also promotes sinusoidal arrangement with increased sinusoidal branch and loop structure.Meanwhile, we found that CD11c + DCs followed a lognormal distribution in the hepatic lobules, skewing toward lobular boundary in steady state.CCl4-induced chronic liver injury promoted CD11c + DC rearrangement at the lobular border before the formation of liver fibrosis.Furthermore, through whole-mount imaging of tumor-immune cell-vascular crosstalk in intact lobes based on liver-CUBIC, we characterized an accumulation of CX3CR1 + CCR2 + F4/80 + macrophages at metastatic foci in early colorectal liver metastases.Importantly, colorectal cells secrete CCL2 to mobilize CX3CR1 + CCR2 + F4/80 + macrophages to accumulate at liver micrometastases, and the interruption of CCL2-induced macrophage accumulation inhibits early colonization of metastasis in the liver.Conclusions: Our investigation of the sinusoidal network and DC/macrophage arrangements through the liver-CUBIC approach and whole-mount imaging provide a powerful platform for understanding hepatic circulatory properties and immune surveillance in the liver.
HER2-targeted dual radiotracer approach with clinical potential for noninvasive imaging of trastuzumab-resistance caused by epitope masking
Authors: Liqiang Li, Tianyu Liu, Linqing Shi, Xin Zhang, Xiaoyi Guo, Biao Hu, Meinan Yao, Hua Zhu, Zhi Yang, Bing Jia, Fan Wang
Journal: Theranostics (2022)

Rationale:The decreased HER2-accessibility by epitope masking is a primary trastuzumab-resistance mechanism.In this study, we developed a HER2-targeted dual radiotracer approach to predict the HER2-trastuzumab engagement noninvasively.Methods: Two novel HER2-specific VHHs, MIRC208 and MIRC213, were acquired by immunizing alpaca with human HER2 protein, and were site-specifically labeled with 99m Tc.Biodistribution and SPECT/CT imaging studies were performed in mice bearing HER2-positive and HER2-negative tumors.The HER2 binding sites of 99m Tc-MIRC208 and 99m Tc-MIRC213 were investigated by cell binding and SPECT/CT imaging studies.We evaluated the therapeutic predictive ability of our dual-radiotracer imaging approach for trastuzumab treatment in mice bearing MUC4-positive tumors (trastuzumab-resistant JIMT-1 and 87MUC4) and MUC4-negative tumors (trastuzumab-sensitive 7HER2 and NCI-N87).The preliminary clinical studies of 99m Tc-MIRC208 were performed in two patients with HER2-positive breast tumors.Results: 99m Tc-MIRC208 and 99m Tc-MIRC213 clearly visualized HER2-positive tumors, but not HER2-negative tumors.99m Tc-MIRC208 competes with trastuzumab for HER2-binding while 99m Tc-MIRC213 recognizes HER2 on an epitope that is not masked by MUC4.The SPECT/CT studies with 99m Tc-MIRC208 and 99m Tc-MIRC213 clearly showed that the MUC4-negative and trastuzumab-sensitive 7HER2 and NCI-N87 tumors had very similar tumor uptake with the SUV208/SUV213 (2 h) ratios of 1.11 ± 0.17 in 7HER2 and 1.25 ± 0.22 in NCI-N87.However, the MUC4-positive JIMT-1 tumors showed the decreased SUV208/SUV213 (2 h) ratio (0.63 ± 0.07), which correlated well with the low response rate to trastuzumab therapy.The SUV208/SUV213 (2 h) ratio was reduced to 0.72 ± 0.02 in MUC4-expressing NCI-N87 cells, and resulting in the decreased trastuzumab sensitivity, further supporting the correlation between the SUV208/SUV213 (2 h) ratio and trastuzumab-sensitivity.The primary and metastatic HER2-positive lesions of patients were clearly visualized by 99m Tc-MIRC208 SPECT at 2 h post injection.Conclusion: Overall, we demonstrated that the dual radiotracer imaging strategy is a valid noninvasive approach for the cancer patient selection before trastuzumab therapy.99m Tc-MIRC213 SPECT is utilized to quantify the tumor HER2 expression and screen HER2-positive cancer patients, while 99m Tc-MIRC208 SPECT is used to determine the HER2-accessibility of trastuzumab.The SUV208/SUV213 (2 h) ratio is an important biomarker to determine the responsiveness of trastuzumab therapy.
Subpial delivery of adeno-associated virus 9-synapsin-caveolin-1 (<i>AAV9-SynCav1</i>) preserves motor neuron and neuromuscular junction morphology, motor function, delays disease onset, and extends survival in hSOD1<sup>G93A</sup> mice
Authors: Shanshan Wang, Taiga Ichinomiya, Paul Savchenko, Dongsheng Wang, Atsushi Sawada, Xiaojing Li, Tiffany Duong, Wenxi Li, Jacqueline A. Bonds, Eun Jung Kim, Atsushi Miyanohara, David M. Roth, Hemal H. Patel, Piyush M. Patel, Takahiro Tadokoro, Martin Marsala, Brian P. Head
Journal: Theranostics (2022)

Elevating neuroprotective proteins using adeno-associated virus (AAV)-mediated gene delivery shows great promise in combating devastating neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is one such disease resulting from loss of upper and lower motor neurons (MNs) with 90-95% of cases sporadic (SALS) in nature. Due to the unknown etiology of SALS, interventions that afford neuronal protection and preservation are urgently needed. Caveolin-1 (Cav-1), a membrane/lipid rafts (MLRs) scaffolding and neuroprotective protein, and MLR-associated signaling components are decreased in degenerating neurons in postmortem human brains. We previously showed that, when crossing our SynCav1 transgenic mouse (TG) with the mutant human superoxide dismutase 1 (hSOD1G93A) mouse model of ALS, the double transgenic mouse (SynCav1 TG/hSOD1G93A) exhibited better motor function and longer survival. The objective of the current study was to test whether neuron-targeted Cav-1 upregulation in the spinal cord using AAV9-SynCav1 could improve motor function and extend longevity in mutant humanized mouse and rat (hSOD1G93A) models of familial (F)ALS. Methods: Motor function was assessed by voluntary running wheel (RW) in mice and forelimb grip strength (GS) and motor evoked potentials (MEP) in rats. Immunofluorescence (IF) microscopy for choline acetyltransferase (ChAT) was used to assess MN morphology. Neuromuscular junctions (NMJs) were measured by bungarotoxin-a (Btx-a) and synaptophysin IF. Body weight (BW) was measured weekly, and the survival curve was determined by Kaplan-Meier analysis. Results: Following subpial gene delivery to the lumbar spinal cord, male and female hSOD1G93A mice treated with SynCav1 exhibited delayed disease onset, greater running-wheel performance, preserved spinal alpha-motor neuron morphology and NMJ integrity, and 10% increased longevity, independent of affecting expression of the mutant hSOD1G93A protein. Cervical subpial SynCav1 delivery to hSOD1G93A rats preserved forelimb GS and MEPs in the brachial and gastrocnemius muscles. Conclusion: In summary, subpial delivery of SynCav1 protects and preserves spinal motor neurons, and extends longevity in a familial mouse model of ALS without reducing the toxic monogenic component. Furthermore, subpial SynCav1 delivery preserved neuromuscular function in a rat model of FALS. The latter findings strongly indicate the therapeutic applicability of SynCav1 to treat ALS attributed to monogenic (FALS) and potentially in sporadic cases (i.e., SALS).
Local administration of liposomal-based Srpx2 gene therapy reverses pulmonary fibrosis by blockading fibroblast-to-myofibroblast transition: Erratum
Authors: Qi Wang, Juan Liu, Yinan Hu, Ting Pan, Yongjian Xu, Jun Yu, Weining Xiong, Qing Zhou, Yi Wang
Journal: Theranostics (2022)

[This corrects the article DOI: 10.7150/thno.61085.].
Targeting the splicing factor NONO inhibits GBM progression through GPX1 intron retention
Authors: Xu Wang, Mingzhi Han, Shuai Wang, Yanfei Sun, Wenbo Zhao, Zhiyi Xue, Xiangjun Liang, Bin Huang, Gang Li, Anjing Chen, Xingang Li, Jian Wang
Journal: Theranostics (2022)

Background: Splicing factors are essential for nascent pre-mRNA processing and critical in cancer progression, suggesting that proteins with splicing functions represent potential molecular targets for cancer therapy.Here, we investigate the role of splicing factors in glioblastoma multiforme (GBM) progression and the possibility of targeting them for the treatment of the disease.Methods: The TCGA and CGGA public databases were used to screen for differentially expressed mRNA splicing factors.Immunohistochemistry and qRT-PCR were used to analyze the expression of non-POU domain-containing octamer-binding protein (NONO), a Drosophila behavior human splicing (DBHS) protein.Knockdown/overexpression of NONO with siRNA and lentiviral expression constructs was used to examine cell growth, apoptosis, and invasion in GBM cells.RNA sequencing was used to identify potential downstream molecular targets of NONO.RIP-PCR and RNA pulldown were used to determine the interaction between NONO and pre-mRNA.JC-1 staining and the seahorse assay were performed to assess redox homeostasis.Results: Expression of NONO was increased in GBM samples and associated with poor survival in patients (P = 0.04).Knockdown of NONO suppressed GBM growth, and overexpression of NONO promoted GBM tumorigenesis in vitro and in vivo.RNA sequencing-based transcriptomic profiling confirmed that knockdown of NONO in U251 and P3 cells resulted in global intron retention of pre-mRNA and led to abnormal splicing of specific pre-mRNAs for GPX1 and CCN1.NONO bound to a consensus motif in the intron of GPX1 pre-mRNA in association with another DBHS protein family member, PSPC1.Knockdown of NONO impaired tumor growth, invasion, and redox homeostasis through aberrant splicing of GPX1.Finally, Auranofin, a small molecule inhibitor of NONO, suppressed GBM tumor growth in an orthotopic xenograft model in mice. Conclusions:We demonstrated that intron retention was a critical alternative RNA splicing event to occur in GBM progression, and that NONO was a key regulator of mRNA splicing in GBM.Targeting NONO represents a novel, potential therapeutic strategy for GBM treatment.
Lgr5<sup>+</sup> cells are required and dynamically participate in olfactory epithelium regeneration: a revisiting shows Lgr5 expression in multiple cell lineages
Authors: Wenwen Ren, Zhenjie Ma, Li Wang, Xiaoyu Feng, Hongmeng Yu, Yiqun Yu
Journal: Theranostics (2022)

Olfactory sensory neurons (OSNs) located in the olfactory epithelium (OE) detect thousands of volatile environmental odors to form the sense of smell. OSNs are generated from basal cells, which show the characteristics of progenitor/stem cells. In the mammalian OE, persistent neurogenesis occurs during lifetime, providing a unique model to study the tissue turnover and fate determination of stem cells. Methods: Immunohistochemical analysis and RNAscope in situ hybridization indicated the localization of leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) in the intact and injured OE. Lineage tracing was conducted to analyze the dynamic role of Lgr5+ cells in the OE homeostasis and regeneration. We also used DTR-driven genetic depletion of Lgr5+ cells and lentivirus-mediated Lgr5 downregulation to demonstrate the essential role of Lgr5+ cells in the OE regeneration. Results: We show that Lgr5 marks horizontal basal cells (HBCs) in the OE of adults but not newborns. We revisit the role of Lgr5+ cells in the OE homeostasis and regeneration, and find that Lgr5+ cells participate in the OE homeostasis from neonatal to one-month-old age, as well as in the OE regeneration post injury. During the OE regeneration, Lgr5 is transiently expressed in apical supporting cells, immature neurons, and mature sensory neurons. The Lgr5+ cells become or generate HBCs in the regenerated OE. DTR-driven cell depletion shows that Lgr5+ cells are not necessary in the adult OE homeostasis, but required in the recovery of OE from injury. Lgr5 down-regulation by lentiviral infection also demonstrates the essential role of Lgr5 expression in the OE regeneration. Conclusion: Our study elucidates the role of Lgr5+ cells in the OE homeostasis and regeneration, potentially providing a candidate to cell-based therapy against olfactory dysfunction.
Co-delivery of phagocytosis checkpoint and STING agonist by a Trojan horse nanocapsule for orthotopic glioma immunotherapy
Authors: Ying Zhou, Yuxin Guo, Lufei Chen, Xiaoli Zhang, Wei Wu, Zhimin Yang, Xuejie Li, Yuanzhuo Wang, Zhiyuan Hu, Zihua Wang
Journal: Theranostics (2022)

Rationale: Cancer immunotherapy has demonstrated significant antitumor activity in a variety of tumors; however, extensive infiltration of immunosuppressive tumor-associated macrophages (TAMs) in the glioblastoma (GBM) tumor microenvironment (TME) and the existence of the blood-brain barrier (BBB) might lead to failure of the checkpoint blockade therapy. Methods: Herein, we have developed a smart "Trojan horse" BBB-permeable nanocapsule termed "NAcp@CD47" to deliver anti-CD47 antibodies and stimulator of interferon genes (STING) agonists into GBM tissues in a stealth-like manner to reshaped the immune microenvironment by switching the phenotype of microglia and macrophages. Results: Both in vitro and in vivo studies demonstrate that NAcp@CD47 could effectively penetrate the BBB, increase the polarization of M1-phenotype TAMs, help reduce tumor immunosuppression, and inhibit the orthotopic GBM growth by phagocytosis of macrophages and microglia. Conclusions: Our findings indicate that the well-designed NAcp@CD47 not only enhances the phagocytosis of cancer cells but also efficiently enhance antitumor immunogenicity and reverses immune suppression to convert uninflamed "cold" tumors into "hot" tumors.
SETD1A-SOX2 axis is involved in tamoxifen resistance in estrogen receptor α-positive breast cancer cells
Authors: Ming Li Jin, Liu Yang, Kwang Won Jeong
Journal: Theranostics (2022)

Rationale: Approximately 30-40% of estrogen receptor (ER)-positive breast cancer (BC) cases recur after tamoxifen therapy.Thus, additional studies on the mechanisms underlying tamoxifen resistance and more specific prognostic biomarkers are required.In this study, we investigated the role of the SET domain containing 1A (SETD1A), a histone H3-lysine 4 (H3K4) methyltransferase, in the development of tamoxifen resistance in BC.Methods: The relationship between tamoxifen resistance and SETD1A protein level was investigated using resistant cell lines derived from the parent BC cells.Biochemical and molecular assays, such as RNA-sequencing, reverse transcription-quantitative polymerase chain reaction, chromatin-immunoprecipitation, and protein-binding assays, were used to identify the SETD1A target gene in tamoxifen-resistant BC cells.Additionally, the role of SETD1A in cancer stem cells (CSCs) was investigated using CSCs isolated from tamoxifen-resistant BC cells.Comprehensive transcriptome analysis and immunofluorescence staining using clinical datasets and tissue microarray were performed to determine the correlation between the expression of the SETD1A-SRY-box transcription factor 2 (SOX2) pair and recurrence in tamoxifen-treated patients with BC.Results: SETD1A was expressed at higher levels in tamoxifen-resistant BC cells than in primary BC cells.Notably, SETD1A-depleted tamoxifen-resistant MCF-7 cells showed restored sensitivity to tamoxifen, whereas SETD1A overexpression in MCF-7 cells resulted in decreased sensitivity.SETD1A is recruited to the SOX2 gene via its interaction with SOX2, thereby enhancing the expression of SOX2 genes in tamoxifen-resistant BC cells.The growth of tamoxifen-resistant cells and CSCs was effectively suppressed by SETD1A knockdown.In addition, high levels of SETD1A and SOX2 were significantly correlated with a low survival rate in patients with ER-positive tamoxifen-resistant BC.Conclusion: Our findings provide the first evidence of the critical role of the SETD1A-SOX2 axis in tamoxifen-resistant BC cells, implying that SETD1A may serve as a molecular target and prognostic indicator of a therapeutic response in patients with tamoxifen-resistant BC.